Substituted β-diketones and their use

ABSTRACT

Compound of formula ##STR1## wherein n is 0 or 1, R 1  and R 2  are independently methyl, ethyl or cyclopropyl and R is an optionally substituted phenyl or heteroaryl group or salt or ester thereof are useful in the treatment of inflammatory bowel disease.

This application is a divisional of application Ser. No. 07/648,641, filed Jan. 31, 1991, now U.S. Pat. No. 5,185,370, which is a continuation-in-part application of PCT/FI89/00165, filed Sep. 1, 1989, which designated the United States.

The present invention relates to substituted β-diketones and their physiologically acceptable salts and esters, which are useful in the treatment of inflammatory bowel diseases.

PCT/FI89/00165 discloses β-diketones, which is herein incorporated by reference, possess cytoprotective efficacy in the stomach and in the duodenum and are useful in the treatment or prophylaxis of gastric and duodenal ulcers.

It has now been found that some substituted β-diketones are especially useful in the treatment of inflammatory bowel diseases (IBD).

The term IBD encompasses chronic inflammatory conditions of the gastrointestinal tract such as Crohn's disease and ulcerative colitis. The exact cause of the disease is still unknown. Infectious agents, immunological abnormalities, permeability disorders and leukotrienes are some of the factors suggested to play a role in the pathogenesis of IBD. The present medical therapy (sulfasalazine, 5-ASA, corticosteroids) is focused only on the diminishing of the inflammatory response, and there is still a great requirement for a more specific and effective drug for the treatment of IBD (Sutherland, CMAJ 137:799-802, 1987).

The present invention provides a method of treatment of inflammatory bowel disease by administering to a patient in need of such treatment an effective amount of a compound of formula I ##STR2## wherein n=0 or 1, R₁ and R₂ are independently methyl, ethyl or cyclopropyl and R is an optionally substituted phenyl or heteroaryl group; ##STR3## wherein X₁ is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X₂ and X₃ are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido or;

    R.sub.3 S(O).sub.m --

wherein m=0, 1 or 2 and R₃ is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl; Y is oxygen or sulfur and X₄ is hydrogen, nitro or halo; or a pharmaceutically acceptable salt or ester thereof.

The present invention also provides a compound according to the general formula II ##STR4## wherein n=0 or 1, R₁ is methyl, ethyl or cyclopropyl and R₂ is ethyl or cyclopropyl and R is ##STR5## wherein X₁ is hydrogen, hydroxy or alkoxy which is optionally substituted by aryl; X₂ and X₃ are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido or;

    R.sub.3 S(O).sub.m --

wherein m=0, 1 or 2 and R₃ is alkyl, aryl or aralkyl; or carbamoyl which is optionally substituted by alkyl, aryl or aralkyl or R₁ and R₂ are methyl and R is ##STR6## where X₁, X₂ and X₃ are as defined above provided that one of X₂ and X₃ is carbamoyl which is optionally substituted by alkyl, aryl or aralkyl, or a pharmaceutically acceptable salt or ester thereof.

The invention also provides a new compound according to the general formula III ##STR7## wherein n is 0 or 1, R₁ is methyl and X₁ is as defined above and X₂ is

    R.sub.3 S(O).sub.m --

wherein m is 1 or 2 and R₃ is alkyl, aryl or aralkyl and X₃ is hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy or a group as defined for X₂ ; or X₂ and X₃ are both nitro or cyano; or X₂ is nitro and X₃ is formyl or halo or, when X₁ is hydroxy, X₂ may be carboxy, or X₂ and X₃ may both be hydrogen when n=0 and X₁ is alkoxy substituted by aryl, or when n=1 and X₁ is hydroxy or alkoxy optionally substituted by aryl; or a pharmaceutically acceptable salt or ester thereof but excluding 3-[(2-chloro-5-nitrophenyl)methylene]-2,4-pentanedione.

The term "alkyl" as employed herein refers to an alkyl group having preferably 1 to 2 carbon atoms.

The term "alkoxy" as employed herein refers to an alkyl residue as defined above linked to an oxygen atom.

The term "aralkyl" as employed herein refers to an alkyl group having aryl, preferably phenyl as the substituent.

The term "aryl" refers to a carbocyclic aromatic group containing form 6 to 10 carbon atoms in the ring portion. The group may be a single ring or fused rings. Specific examples are phenyl and naphthyl.

The term "heteroaryl" refers to monocyclic or bicyclic aromatic group containing one or more heteroatoms such as nitrogen, oxygen or sulfur.

The preparation of compounds according to the formulae I and II may be carried out in a similar way as described in PCT/FI89/00165 For example the compounds of formula I may be prepared by reacting a compound of the formula IV

    R.sub.1 --CO--CH.sub.2 --CO--R.sub.2                       IV

in which R₁ and R₂ are as defined above with a compound of formula V

    R--(CH═CH).sub.n --Z                                   V

in which n and R are as defined above and Z is CHO or --CH₂ --Q, wherein Q is halogen or some other activated group, in the presence of acidic or basic catalyst to produce a compound of formula I or a compound of formula VI ##STR8## in which n, R₁, R₂ and R are as defined above, which compound is halogenated to give a compound of the formula VII ##STR9## in which n, R₁, R₂ and R are as defined above and X is halogen and dehydrohalogenating compound VII to produce a compound of the formula I.

The basic catalyst may be for example an organic or inorganic base. The acidic catalyst may be for example a mineral or sulfonic acid. The activated group Q may be a halogen or an alkyl or aryl sulfonate.

When halogenating a compound of formula VI elementary halogen, preferably chlorine or bromine may be used, or another known halogenating agent such as sulfuryl chloride may be used.

Salts of these compounds may be prepared by known methods. Most commonly used pharmaceutically acceptable salts are sodium, potassium, ammonium, calcium and magnesium salts and hydrochlorides or hydrobromides. Preferred esters of the compounds of formula I are acyl or aroyl derivatives which will hydrolyse under physiological conditions.

The above compounds may be formulated to dosage forms using the principles which are known to those having average skill in the art. Suitable solvents, gel forming ingredients, dispersion agents, antioxidants and colorants may be added in a normal way.

It is preferred to administer the compounds enterally. When they are given orally, they may be in the form of tablets, granules, capsules, emulsions, suspensions or solutions. It is often advisable to use coated tablets or granules, i.e. so called enterocoated preparations, to ensure that the medicine reaches the desired part of the gastrointestinal tract. Alternatively, the compositions may be given rectally in the form of enemas or suppositories.

The effective dose varies considerably depending on location, degree and severity of the disease being treated as well as the age and the general condition of the patient. The effective dose is generally from about 20 to 1000 mg per day, preferably from 50 to 250 mg per day for an adult, once a day or divided into two to five doses.

In Vivo Tests

The efficacy of the compounds can be demonstrated by using a model of chronic colonic inflammation in the rat, TNB-induced chronic colitis. TNB-induced chronic colonic inflammation in rats is an animal model which has been shown to resemble human IBD.

20 mg of TNB (2,4,6-trinitrobenzenesulfonic acid) in 50% ethanol was administered into the lumen of the colon via a rubber catheter inserted rectally to Wistar rats. The test compounds were given rectally 1 h prior and 24, 48, 72 and 95 h after TNB. The rats were sacrificed 96 h after TNB and their colons were scored according to occurence of ulcers and inflammation. The number of animals in each group was at least 8. 5-ASA (5-aminosalicylic acid), a clinically used drug for the treatment of IBD was used as a reference compound. The results are presented in the Table 1.

                  TABLE 1                                                          ______________________________________                                         The effect of test compounds on the damage score of chronic                    inflammation induced by TNB.                                                                   Dose    % inhibition                                           Test compound   mg/kg   against control                                        ______________________________________                                         5-ASA           100     24                                                     1               30      37                                                     2               30      28                                                     3               10      18                                                                     30      57                                                     4               30      54                                                     5               30      43                                                     6               30      41                                                     7               10      60                                                                     30      48                                                     8               10      51                                                                     30      62                                                     9               30      40                                                     10              10      27                                                     11              30      32                                                     12              30      52                                                     13              30      58                                                     14              30      30                                                     ______________________________________                                    

Test Compounds

1 3-(4-hydroxyphenyl)methylene-2,4-pentanedione

2 3-(4-methoxyphenyl)methylene-2,4-pentanedione

3 3-(3-nitrophenyl)methylene-2,4-pentanedione

4 3-(4-trifluoromethylphenyl)methylene-2,4-pentanedione

5 3-(4-nitrophenyl)methylene-2,4-pentanedione

6 3-(2-nitrophenyl)methylene-2,4-pentanedione

7 3-(4-cyanophenyl)methylene-2,4-pentanedione

8 3-(3-cyanophenyl)methylene-2,4-pentanedione

9 3-[(4-(N-phenethyl)carboxamido-phenyl)methylene]-2,4-pentanedione

10 3-[(5-nitrofuryl)methylene]-2,4-pentanedione

11 4-[(4-cyanophenyl)methylene]-3,5-heptanedione

12 2-[(4-cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

13 2-[(3-trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

14 2-[(4-carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

The test compounds significantly decreased the ulceration and inflammation of the colons. The test compounds were much more potent than the reference compound 5-ASA and should therefore be more effective than 5-ASA in the treatment of human IBD.

The following examples illustrate the production of compounds of use according to the invention.

EXAMPLE 1 3-[(4-Phenylsulfonylphenyl)methylene]-2,4-pentanedione

To a solution containing 2.1 g of 4-phenylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione in 10 ml of 2-propanol was added 1 ml of thionyl chloride with stirring at 20° C. The solution was stirred for 1 h at 20° C. and evaporated to dryness in vacuo. The residue was crystallized from toluene, mp 102°-105° C.

EXAMPLE 2 3-[(4-Methylsulfonylphenyl)methylene]-2,4-pentanedione

The procedure described in Example 1 was repeated by using 1.1 g of 4-methylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione. The product was crystallized from ether, mp 139°-140° C.

EXAMPLE 3 3-[(4-Carboxamidophenyl)methylene]-2,4-pentanedione

A mixture containing 1.8 g of 4-carboxamidobenzaldehyde, 1.1 g of 2,4-pentanedione, 0.2 g of piperidine and 0.2 g of acetic acid in 40 ml of toluene was refluxed for 3 h by using a Dean-Stark separator. The warm clean toluene solution was decanted from the tarry residue and cooled. The crystalline product was filtered and dried. Mp 154°-155° C.

EXAMPLE 4 4-[(4-Nitrophenyl)methylene]-3,5-heptanedione

The procedure described in Example 1 was repeated by using 1.5 g of 4-nitrobenzaldehyde and 2.0 g of 3,5-heptanedione. Yield 1.7 g, yellow oil.

EXAMPLE 5 3-[(3,4-Dichlorophenyl)methylene]-2,4-pentanedione

The procedure described in Example 1 was repeated by using 4.26 g of 3,4-dichlorobenzaldehyde and 3.0 g of 2,4-pentanedione. Yield 1.3 g, mp 73° C.

EXAMPLE 6 3-[(4-Chloro-3-nitrophenyl)methylene]-2,4-pentanedione

The procedure described in Example 1 was repeated by using 1.85 g of 4-chloro-3-nitrobenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.32 g, mp 110°-111° C.

EXAMPLE 7 3-[(4-(N-phenethyl)carboxamidophenyl)methylene]-2,4-pentanedione.

The procedure described in Example 1 was repeated by using 2.5 g of 4-(N-phenethyl)carboxamidobenzaldehyde and 1.0 g of 2,4-pentanedione. Yield 0.5 g, mp 146°-149° C.

EXAMPLE 8 3-[(4-Formyl-3-nitrophenyl)methylene]-2,4-pentanedione

To a solution containing 1.84 g of 2-nitroterephtaldicarboxaldehyde and 1.00 g of 2,4-pentanedione in 10 ml trifluoroacetic acid were added 0.9 ml of thionyl chloride and a catalytic amount of water. The solution was stirred for 2 h at 20° C. 30 ml of water was added and the mixture was extracted with ether. The ether extract was washed several times with Na₂ CO₃ -solution and dried over K₂ CO₃. After filtration the solvent was evaporated in vacuo. The product was purified by column chromatography. Yield 0.2 g, mp 102°-104° C.

EXAMPLE 9 3-[(3,5-Dinitro-4-hydroxyphenyl)methylene]-2,4-pentanedione.

The procedure described in Example 1 was repeated by using 2.12 g of 3,5-dinitro-4-hydroxybenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.9 g, mp 158° C.

EXAMPLE 10 3-1(3,5-Dinitrophenyl)methylene]-2,4-pentanedione

The procedure described in Example 1 was repeated by using 2.53 g 3,5-dinitrobenzaldehyde and 2.43 g of 2,4-pentanedione. Yield 0.8 g, mp 101°-105° C.

EXAMPLE 11 3-[3-(4-Methoxyphenyl)propenylene]-2,4-pentanedione

To a solution containing 2.45 g of 4-methoxycinnamaldehyde in 90 ml of toluene was added 2.2 g of 2,4-pentanedione, 0,26 g of piperidine and 0.45 9 of acetic acid. The solution was refluxed in N₂ atmosphere for 1 h and the water formed in the reaction was azeotropically distilled off by using a Dean-Stark water separator. The solution was evaporated to dryness in vacuo. The residue was trifurated with ether. The crystals were filtered. Yield 0.65 g, mp 108°-110° C.

EXAMPLE 12 3-[(S-Nitrofuryl)methylene]-2,4-pentanedione

A solution containing 2.43 g of 5-nitro-2-furanecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione and 0.1 g of water in 5 ml of tetrahydrofurane was saturated with hydrogen chloride gas at 20° C. The mixture was stirred for 1 h and evaporated to dryness in vacuo. The product was recrystallized from acetic acid. Yield 0.1 g, mp 117°-120° C.

EXAMPLE 13 3-[(S-Nitrothienyl)methylene]-2,4-pentanedione

The procedure described in Example 12 was repeated by using 2.59 g of 5-nitro-2-thiophenecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione. Yield 0.5 g, yellow viscous oil.

EXAMPLE 14 3-(3-Pyridylmethylene)-2,4-pentanedione

The procedure described in Example 3 was repeated by using 3.21 g of pyridine-3-carboxaldehyde and 3.3 g of 2,4-pentanedione. Yield 2.95 g, mp 52°-57° C.

EXAMPLE 15 3-(4-Pyridylmethylene)-2,4-pentanedione hydrochloride

A solution containing 1.1 g of pyridine-4-carboxaldehyde and 1.0 g of 2,4-pentanedione in 10 ml of N,N-dimethylformamide was saturated with hydrogen chloride gas at 20° C. The solution was stirred for 1 h at 20° C. and then for 2 h at 80° C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.17 g, mP 175°-186° C.

EXAMPLE 16 3-(3-Quinolylmethylene)-2,4-pentanedione hydrochloride

The procedure described in Example 3 was repeated by refluxing 2.4 g quinoline-3-aldehyde, 6.6 g 2,4-pentanedione, 0.4 g piperidine and 0.8 g acetic acid in 100 ml toluene. Yield 1.4 g, mp 99°-101° C.

EXAMPLE 17 3-[(3-Carboxy-4-hydroxyphenyl)methylene]-2,4-pentanedione

A mixture containing 2 g 3-carboxy-4-hydroxybenzaldehyde, 4 ml 2,4-pentanedione and 20 ml tetrahydrofuran was saturated with hydrogen chloride gas. The solution was stirred for 2.0 h at 50° C. and evaporated to dryness in vacuo. The residue was crystallized from ethyl ether, mp. 112°-114° C.

EXAMPLE 18 3-[[(4-(2-Phenylethoxy)phenyl]methylene]-2,4-pentanedione

The procedure described in example 8 was repeated by using 5.9 g of 4-(2-phenylethoxy)benzaldehyde, 3.9 ml of 2,4-pentanedione, 26 ml of trifluoroacetic acid and 2.1 ml of thionyl chloride. Yield 4.7 91 an viscous oil.

EXAMPLE 19 2-[(4-Acetamidophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

A mixture containing 1.6 g 4-acetamidobenzaldehyde, 1.5 g 1,3-dicyclopropyl-1,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid in 50 ml of toluene was refluxed for 3 h by using a Dean-Stark separator. After standing over night at room temperature the crystals were filtered and washed with toluene. The product was recrystallized from ethanol. Yield 2.0 g, mp 166°-167° C.

EXAMPLE 20 2-[(4-Methoxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

The procedure described in Example 19 was repeated by using 0.68 g 4-methoxybenzaldehyde and 0.77 g 1,3-dicyclopropyl-1,3-propanedione. Yield 0.46 g, mp 60.5°-61.5° C.

EXAMPLE 21 4-[(3-Cyano phenyl)methylene]-3,5-heptanedione

The procedure described in Example 19 was repeated by using 1.82 g 3-cyanobenzaldehyde and 3.5 g 3,5-heptanedione. Yield 0.4 g, mp 51°-52° C.

EXAMPLE 22 4-1(4-Cyanophenyl)methylene]-3,5-heptanedione

The produre described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 5.0 g 3,5-heptanedione. Yield 2.8 g, mp 59°-60° C.

EXAMPLE 23 3-[(4-Cyanophenyl)methylene]-4-cyclopropyl-2,4-butanedione

The procedure described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 2.5 g 4-cyclopropyl-2,4-butanedione. The product was purified by column chromatography. Yield 0.37 g, mp 83°-85° C.

EXAMPLE 24 2-[(4-Cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

The procedure described in Example 19 was repeated by using 3.78 g 4-cyanobenzaldehyde and 2.23 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.5 9, mp 100°-102° C.

EXAMPLE 25 3-[(5-Bromothienyl)methylene]-2,4-pentanedione

To a solution containing 5.73 g 5-bromothiophene-2-carboxaldehyde and 5.0 g 2,4-pentanedione in 25 ml of 2-propanol, 2.9 ml thionylchloride was gradually added. The mixture was stirred for 2 h at 20° C. 120 ml of conc. Na₂ SO₄ -solution was then added and the mixture was extracted with ether. The solvent was evaporated in vacuo and the crystalline residue was washed with cold ether. Yield 3.9 g, mp 70°-74° C.

EXAMPLE 26 2-[(3-Trifluoromethylphenyl)methylene]-1,3-dicyclopropyl-1,3-2-propanedione

The procedure described in Example 19 was repeated by using 2.15 ml 3-trifluoromethylbenzaldehyde and 2.42 g 1,3-dicyclopropyl-1,3-propanedione. Yield 2.71 g, mp 56°-58° C.

EXAMPLE 27 2-[(4-Carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione

The procedure described in Example 19 was repeated by using 3.0 g 4-carboxybenzaldehyde and 3.06 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.7 g, mp 175°-178° C. in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. Yield 5,3 g (41%).

EXAMPLE 28 3-(4-Trifluoromethylbenzylidene)-2,4-pentanedione

4-Trifluoromethylbenzaldehyde (8,7 g) was condenced with 2,4-pentanedione (5,01 g in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. The crude product was crystallized from a mixture of ether-petroleum ether (1:1), mp 46°-48° C., yield 3,8 g (30 %).

EXAMPLE 29 3-(3-Cyanobenzylidene)-2,4-pentanedione

3-cyanobenzaldehyde (2,62 g) was condenced with 2,4-pentanedione (3,0 g) in 2-propanol (10 ml) in the presence of ammonium acetate. Mp 63°-64° C., yield 1,27 g (30%).

EXAMPLE 30 3-(4-Cyanobenzylidene)-214-pentanedione

4-Cyanobenzaldehyde (2,62 g) was condenced with 2,4-pentanedione (3,0 g) in 2-propanol (10 ml) in the presence of ammonium acetate. Mp 86°-88° C., yield 0,55 g (13%). 

We claim:
 1. A method of treatment of inflammatory bowel disease by administering to a patient in need of such treatment a therapeutically effective amount of the compound of formula I ##STR10## wherein n is 0 or 1, R₁ and R₂ are independently methyl, ethyl or cyclopropyl and R is an unsubstituted or substituted phenyl; ##STR11## wherein X₁ is hydrogen, hydroxy or C₁₋₂ alkoxy which is unsubstituted or substituted by carbocyclic aryl; X₂ and X₃ are independently hydrogen, nitro, cyano, halo, trifluoromethyl, formyl, carboxy, acetamido, or the group

    R.sub.3 S(O).sub.m --

wherein m is 0, 1 or 2 and R₃ is C₁₋₂ alkyl, carbocyclic aryl or carbocyclic aryl C₁₋₂ alkyl; or carbamoyl which is unsubstituted or substituted by C₁₋₂ alkyl, carbocyclic aryl C₁₋₂ alkyl, aryl, or R is one of the following heteroaryl groups; ##STR12## wherein Y is oxygen or sulfur and X₄ is hydrogen, nitro or halo; or a pharmaceutically acceptable salt or ester thereof to treat inflammatory bowel disease.
 2. The method according to claim 1, in which, in the compound of formula I, X₁ is hydroxy or alkoxy.
 3. The method according to claim 1, in which, in the compound of formula I, one of X₂ and X₃ is nitro, cyano, trifluoromethyl, carboxy or carbamoyl which is substituted by carbocyclic aryl.
 4. The method according to claim 1, wherein the compound is selected from the group comprising3-(4-hydroxyphenyl)methylene-2,4-pentanedione, 3-(4-methoxyphenyl)methylene-2,4-pentanedione, 3-(3-nitrophenyl)methylene-2,4-pentanedione, 3-(4-nitrophenyl)methylene-2,4-pentanedione, 3-(2-nitrophenyl)methylene-2,4-pentanedione, 3-[(4-(N-phenethyl)carboxamido-phenyl)methylene]-2,4-pentanedione, 3-[(5-nitrofuryl)methylene]-2,4-pentanedione, and 2-[(4-carboxyphenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione or a pharmaceutically acceptable salt or ester thereof.
 5. The method according to claim 1, wherein the compound is 3-(4-trifluoromethylphenyl)methylene-2,4-pentanedione.
 6. The method according to claim 1, wherein the compound is 3-(4-cyanophenyl)methylene-2,4-pentanedione.
 7. The method according to claim 1, wherein the compound is 3-(3-cyanophenyl)methylene-2,4-pentanedione.
 8. The method according to claim 1, wherein the compound is 4[(4-cyanophenyl)methylene]-3,5-heptanedione.
 9. The method according to claim 1, wherein the compound is 2-[(4-cyanophenyl)methylene]-1,3-dicyclopropyl-1,3-propanedione.
 10. The method according to claim 1, wherein the compound is 2-[(3-trifluoromethylphenyl)methylene]-1,3-di-cyclopropyl-1,3-propanedione
 11. The method according to claim 1, wherein the inflammatory bowel disease is ulcerative colitis.
 12. The method according to claim 1, wherein the inflammatory bowel disease is Crohn's disease. 